Opioid receptors are a group of inhibitory G protein-coupled receptors with to opioids as ligands. Opioid receptors are distributed widely in the brain, and are found in the spinal cord and digestive tract. The types of opioid receptors are mu (μ) MOR, kappa (κ) KOR, and delta (δ) DOR. The receptors were generally named using the first letter of the first ligand that was found to bind to them. For instance, morphine was the first chemical shown to bind to mu receptors. The first letter of the drug morphine is m, rendered as the corresponding Greek letter μ. In similar manner, a drug known as ketocyclazocine was first shown to interact with kappa receptors, while the delta receptor was named after the mouse vas deferens tissue in which the receptor was first characterized. The mu receptor is the primary target of currently used narcotic analgesics.
The opioid receptor types are ˜70% identical with substantial differences located at N and C termini as well as other regions of the receptors. It is thought that the G protein binds to the third intracellular loop of the opioid receptors. Both in mice and humans, the genes for the various receptor subtypes are located on different chromosomes.
Some characteristics of the MOR, KOR, and DOR are presented below.
The mu (μ) opioid receptor (MOR) is found in the brain (e.g., in the cortex (laminae III and IV), thalamus, striosomes, periaqueductal gray, and rostral ventromedial medulla), in the spinal cord (e.g., in the substantia gelatinosa), in the peripheral sensory neurons, and in the intestinal tract. The mu receptor has roles in analgesia, physical dependence, respiratory depression, miosis, euphoria, reduced gastrointestinal motility, physical dependence, and possible vasodilation.
The kappa (κ) opioid receptor (KOR) is found in the brain (e.g., in the hypothalamus, periaqueductal gray, and claustrum), in the spinal cord (e.g., in the substantia gelatinosa) and in the peripheral sensory neurons. Kappa opioid receptors play a role in analgesia, anticonvulsant effects, depression, dissociative/hallucinogenic effects, diuresis, dysphoria, miosis, neuroprotection, sedation, and stress.
The delta (δ) opioid receptor (DOR) is found in the brain (e.g., in the pontine nuclei, amygdala, olfactory bulbs, deep cortex) and in the peripheral sensory neurons. Delta opioid receptors play a role in analgesia, antidepressant effects, convulsant effects, physical dependence, and may modulate μ-opioid receptor-mediated respiratory depression
The macrocyclic peptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp] (SEQ ID NO: 1) exhibits mixed opioid agonist/kappa opioid receptor (KOR) antagonist activity in vivo and is a promising lead compound for developing novel therapeutics for the treatment of pain and drug abuse. We synthesized analogs of this lead peptide to explore the influence of the aromatic residues on the analogs' opioid activity profiles.